Intrauterine Zn deficiency favors thyrotropin-releasing hormone-increasing effects on thyrotropin serum levels and induces subclinical hypothyroidism in weaned rats

Individuals who consume a diet deficient in zinc (Zn-deficient) develop alterations in hypothalamic-pituitary-thyroid axis function, i.e., a low metabolic rate and cold insensitivity. Although those disturbances are related to primary hypothyroidism, intrauterine or postnatal Zn-deficient adults have an increased thyrotropin (TSH) concentration, but unchanged thyroid hormone (TH) levels and decreased body weight. This does not support the view that the hypothyroidism develops due to a low Zn intake. In addition, intrauterine or postnatal Zn-deficiency in weaned and adult rats reduces the activity of pyroglutamyl aminopeptidase II (PPII) in the medial-basal hypothalamus (MBH). PPII is an enzyme that degrades thyrotropin-releasing hormone (TRH). This hypothalamic peptide stimulates its receptor in adenohypophysis, thereby increasing TSH release. We analyzed whether earlier low TH is responsible for the high TSH levels reported in adults, or if TRH release is enhanced by Zn deficiency at weaning. Dams were fed a 2 ppm Zn-deficient diet in the period from one week prior to gestation and up to three weeks after delivery. We found a high release of hypothalamic TRH, which along with reduced MBH PPII activity, increased TSH levels in Zn-deficient pups independently of changes in TH concentration. We found that primary hypothyroidism did not develop in intrauterine Zn-deficient weaned rats and we confirmed that metal deficiency enhances TSH levels since early-life, favoring subclinical hypothyroidism development which remains into adulthood

Mediobasal hypothalamic and adenohypophyseal TRH-degrading enzyme (PPII) is down-regulated by zinc deficiency

Thyrotropin-releasing hormone (TRH) synthesized in hypothalamic paraventricular nucleus directs hypothalamus-pituitary-thyroid (HPT) axis function, regulating thyrotropin release from adenohypophysis and thyroid hormones serum concentration. Pyroglutamyl aminopeptidase II (PPII), a Zn-dependent metallopeptidase located in adenohypophysis and medial-basal-hypothalamus degrades TRH released from the median eminence and participates in HPT axis function by regulating TRH-induced thyrotropin release from adenohypophysis. It is unknown whether dietary Zn deficiency down-regulates PPII. Our aim was to compare adenohypohyseal and medial-basal-hypothalamic PPII activity and expression of adult rats fed a Zn-deficient diet (2 ppm) throughout their lifespan (DD), prenatally (DC) or after weaning (CD) vs. that of animals fed a control diet (20 ppm:CC). Female rats consumed a Zn-deficient or control diet from two weeks before gestation and up to the end of lactation. We analyzed adenohypophyseal and medial-basal-hypothalamic PPII activity of dams and male offspring when adults; its relation to median eminence TRH, serum thyrotropin, leptin and thyroid hormones concentration. Offspring ate the same diet as their dams (CC, DD) or were switched from dietary regime after weaning (CD, DC) and until 2.5 months of age. DD males showed decreased adenohypophyseal and medial-basal-hypothalamic PPII activity, along with high thyrotropin serum concentration. Post-weaning Zn-deficiency (CD) decreased PPII activity only in adenohypophysis and increased thyrotropin circulating levels. Zn-replenishment (DC) normalized PPII activity in both regions and serum thyrotropin concentration. Adenohypophyseal PPII activity decreased and prolactin levels increased in Zn-deficient dams. We concluded that long-term changes in dietary Zn down-regulate PPII activity independently of T3, increasing thyrotropin serum concentration, overall resembling sub-clinical hypothyroidism

Mct8 and trh co-expression throughout the hypothalamic paraventricular nucleus is modified by dehydration-induced anorexia in rats

Thyrotropin-releasing hormone (TRH) is a neuropeptide with endocrine and neuromodulatory effects. TRH from the paraventricular hypothalamic nucleus (PVN) participates in the control of energy homeostasis; as a neuromodulator TRH has anorexigenic effects. Negative energy balance decreases PVN TRH expression and TSH concentration; in contrast, a particular model of anorexia (dehydration) induces in rats a paradoxical increase in TRH expression in hypophysiotropic cells from caudal PVN and high TSH serum levels, despite their apparent hypothalamic hyperthyroidism and low body weight. We compared here the mRNA co-expression pattern of one of the brain thyroid hormones' transporters, the monocarboxylate transporter-8 (MCT8) with that of TRH in PVN subdivisions of dehydration-induced anorexic (DIA) and control rats. Our aimwas to identify whether a lowMCT8 expression in anorexic rats could contribute to their high TRHmRNAcontent.Weregistered daily food intake and body weight of 7-day DIA and control rats and analyzed TRH and MCT8 mRNA co-expression throughout the PVN by double in situ hybridization assays. We found that DIA rats showed increased number of TRHergic cells in caudal PVN, as well as a decreased percentage of TRH-expressing neurons that co-expressedMCT8mRNA signal. Results suggest that the reduced proportion of double TRH/MCT8 expressing cells may be limiting the entry of hypothalamic triiodothyronine to the greater number of TRH-expressing neurons from caudal PVN and be in part responsible for the high TRH expression in anorexia rats and for the lack of adaptation of their hypothalamic-pituitary-thyroid axis to their low food intake.This work was supported by CONACYT128316 (P. de Gortari) and by MINECOPI-10/01874, CIBERNED and Generalitat de CatalunyaSGR2009/220 (G. Mengod).Peer Reviewe

Testing the Challenge Hypothesis in Stumptail Macaque Males: The Role of Testosterone and Glucocorticoid Metabolites in Aggressive and Mating Behavior

The “challenge hypothesis” predicts higher male–male aggressive behavior along with increases in testosterone levels during times of reproductive challenges and social instability. In addition, in some primate species, higher glucocorticoid levels can be observed as well, but this is usually modulated by dominance rank. We studied rank-related aggressive behavior, mating activity, and fecal testosterone and glucocorticoid metabolites (fTm and fGCm) in male stumptail macaques (Macaca arctoides) in order to test some predictions of the “challenge hypothesis”. Over a 20-month period, we collected data on aggressive behavior and copulation, as well as fecal samples (n = 700) to quantify fTm and fGCm in seven adult stumptail males living in captivity. During periods of mating activity, male-to-male aggression increased in higher- and middle-ranking males. Neither fTm nor fGCm levels predicted male-to-male aggression. fGCm levels (but not fTm) were positively associated with male-to-female aggression; however, this association was pronounced during periods of mating activity. fGCm levels differed according to social rank, with middle-ranking males having the highest levels. Both hormones were higher during periods of mating activity, but only in higher- and middle-ranking males. Taken together, our findings partially support the challenge hypothesis in a non-seasonal primate and shed some light on the unique social and mating system of the stumptail macaque